Cough Receptor Sensitivity Research Articles

Effects of spray cryotherapy on cough receptors and airway microenvironment in a canine model of chronic bronchitis

The aim of this study was to explore the effects of spray cryotherapy (SCT) on cough receptors and airway microenvironment in a canine model of chronic bronchitis. We examined the expression of transient receptor potential vanilloid 1/4 (TRPV1/4) and the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) at the gene and protein levels before and after SCT. In addition, we explored whether TRPV1/4 could regulate inflammatory factors via mediator adenosine triphosphate (ATP). The levels of ATP and cytokines in alveolar lavage fluid and cell supernatant were measured using ELISA. SCT effectively downregulated the expression of TRPV1/4 and SP/CGRP in canine airway tissues with chronic bronchitis and reduced the levels of inflammatory mediators and cytokines that affect cough receptor sensitivity, achieving cough relief. TRPV1/4 - ATP - inflammatory cytokines axis has been demonstrated at the cellular level, which in turn modulate the milieu of the airways and promote the formation of a cough feedback loop. Our study has fully revealed the specific mechanism of SCT in treating cough in a canine model of chronic bronchitis, providing a solid theoretical basis for future clinical treatment.

Real-life effectiveness of indacaterol/glycopyrronium/mometasone for symptomatic relief of cough after switching from inhaled corticosteroid/long-acting β2-agonist therapy in patients with asthma: REACH study design.

Cough is a major symptom in patients with asthma and poses a significant burden compared with other asthma symptoms. However, there are no approved treatments in Japan, developed to specifically treat cough in patients with asthma. We present the design of REACH, an 8-week real-life study, which will evaluate the efficacy of a combination of indacaterol acetate, glycopyrronium bromide and mometasone furoate (IND/GLY/MF) in asthmatic patients with cough refractory to medium-dose inhaled corticosteroid/long-acting β2-agonist (ICS/LABA). Patients with asthma (age ≥20 to <80 years) with a cough visual analogue scale (VAS) ≥40 mm will be randomised 2:1:1 to receive IND/GLY/MF medium-dose 150/50/80 μg once daily or step-up to a high-dose regimen of fluticasone furoate/vilanterol trifenatate (FF/VI) 200/25 µg once daily or budesonide/formoterol fumarate (BUD/FM) 160/4.5 µg four inhalations twice daily during the 8-week treatment period. The primary objective is to demonstrate the superiority of IND/GLY/MF medium-dose over high-dose ICS/LABA in terms of cough-specific quality of life after 8 weeks. The key secondary objective is to demonstrate the superiority of IND/GLY/MF in terms of subjective assessment of cough severity. Cough frequency (VitaloJAK cough monitor) and capsaicin cough receptor sensitivity will be evaluated in eligible patients. Cough VAS scores, fractional exhaled nitric oxide, spirometry and blood tests, and the Asthma Control Questionnaire-6, Cough and Sputum Assessment Questionnaire, and Japanese version of the Leicester Cough Questionnaire will be evaluated. REACH will provide valuable evidence on whether a switch to IND/GLY/MF medium-dose or step-up to high-dose ICS/LABA is beneficial for patients with persistent cough despite treatment with medium-dose ICS/LABA.

Increased Cough Receptor Sensitivity to Capsaicin Predicts a Positive Bronchial Thermoplasty Response: A Single-center Retrospective Study.

Bronchial thermoplasty (BT) is a novel bronchoscopic therapy for severe uncontrolled asthma unresponsive to standard pharmacological treatments, including inhaled corticosteroids and long-acting beta-2 agonists. Although several studies have shown that BT improves asthma control, the optimal predictors of BT response remain unknown. We reviewed 10 consecutive asthma patients treated with BT at Kanazawa University Hospital between January 2016 and March 2018 and attempted to identify factors that correlated with a positive BT response. All patients had the most severe persistent asthma according to the 2017 Japanese guidelines for adult asthma and were uncontrolled despite adequate treatments including high-dose inhaled corticosteroids and long-acting beta-2 agonists. Six patients had significant improvement in asthma control evaluated with the Asthma Control Questionnaire-6. Eight patients showed a significant improvement in asthma-specific health-related quality of life evaluated with the Asthma Quality of Life Questionnaire. The number of severe asthma exacerbations decreased in 6 patients. The maintenance dose of oral corticosteroids decreased in 1 patient. There were no severe adverse events related to the procedure. Six patients showed a positive BT response, and all 4 patients with increased cough receptor sensitivity to capsaicin responded to BT. No other factors, including age, smoking status, body mass index, age of asthma onset, disease duration, blood eosinophil count, total serum immunoglobulin E, prebronchodilator forced expiratory volume in 1 second, reversibility to beta-2 agonist, or fractional exhaled nitric oxide, were associated with a positive BT response. Increased cough receptor sensitivity to capsaicin may predict a positive BT response.

Clinical, Physiological and Anti-Inflammatory Effect of Montelukast in Patients with Cough Variant Asthma

Background: Cough variant asthma (CVA) is a phenotype of asthma presenting solely with coughing, characterized by airway hyperresponsiveness, eosinophilic inflammation and a cough response to bronchodilators. Leukotriene receptor antagonists (LTRAs) are antiasthma medications with anti-inflammatory and bronchodilatory properties. Although LTRAs exert antitussive effects in CVA, the mechanisms involved are unknown. Objectives: This study aimed to clarify the antitussive mechanisms of LTRAs in CVA patients. Methods: We prospectively observed the effect of montelukast (10 mg) daily for 4 weeks in 23 consecutive nonsmoking adults with anti-inflammatory treatment-naive CVA. We evaluated, before and after treatment, the cough visual analogue scale (VAS), pulmonary function (spirometry and impulse oscillation), methacholine airway responsiveness, cough receptor sensitivity, expressed by the concentration of capsaicin inducing 2 or more (C2) and 5 or more (C5) coughs, sputum eosinophil counts and levels of inflammatory mediators, including cysteinyl leukotrienes, leukotriene B₄, prostaglandin (PG) D₂, PGE₂, PGF₂_α and thromboxane B₂. We compared the baseline characteristics of the patients based on the symptomatic response to montelukast, defined as a decrease in the cough VAS of >25% (n = 15) or ≤25% (n = 8). Results: Montelukast significantly decreased the cough VAS (p = 0.0008), sputum eosinophil count (p = 0.013) and cough sensitivity (C2: p = 0.007; C5: p = 0.039), whereas pulmonary function, airway responsiveness and sputum mediator levels remained unchanged. Multivariate analysis showed that a better response to montelukast was associated solely with younger age (p = 0.032). Conclusion: The antitussive effect of montelukast in CVA may be attributed to the attenuation of eosinophilic inflammation rather than its bronchodilatory properties.

Do Sex and Atopy Influence Cough Outcome Measurements in Children?

Despite the commonality of cough and its burden, there are no published data on the relationship between atopy or sex on objectively measured cough frequency or subjective cough scores in children. In 202 children with and without cough, we determined the effect of sex and atopy on validated cough outcome measurements (cough receptor sensitivity [CRS], objective cough counts, and cough scores). We hypothesized that in contrast to adult data, sex does not influence cough outcome measures, and atopy is not a determinant of these cough measurements. We combined data from four previous studies. Atopy (skin prick test), the concentration of capsaicin causing two and five or more coughs (C2 and C5, respectively), objectively measured cough frequency, and cough scores were determined and their relationship explored. The children's (93 girls, 109 boys) mean age was 10.6 years (SD 2.9), and 56% had atopy. In multivariate analysis, CRS was influenced by age (C2 coefficient, 5.9; P = .034; C5 coefficient, 29.1; P = .0001). Atopy and sex did not significantly influence any of the cough outcomes (cough counts, C2, C5, cough score) in control subjects and children with cough. Atopy does not influence important cough outcome measures in children with and without chronic cough. However, age, but not sex, influences CRS in children. Unlike adult data, sex does not affect objective counts or cough score in children with and without chronic cough. Studies on cough in children should be age matched, but matching for atopic status and sex is less important.

Effect of Smoking on Cough Reflex Sensitivity: Basic and Preclinical Studies

In healthy nonsmokers, inhalation of one single puff of cigarette smoke immediately evoked airway irritation and cough, which were either prevented or markedly diminished after premedication with hexamethonium. Single-fiber recording experiments performed in anesthetized animals showed that both C fibers and rapidly adapting receptors in the lungs and airways were stimulated by inhalation of one breath of cigarette smoke. Application of nicotine evoked an inward current and triggered depolarization and action potentials in a concentration-dependent manner in a subset of isolated vagal pulmonary sensory neurons. Taken together, these studies showed that activation of the nicotinic acetylcholine receptors expressed on airway sensory nerves is mainly responsible for the acute airway irritation and cough reflex elicited by inhaled cigarette smoke. Chronic exposure to cigarette smoke consistently induces enhanced cough responses to various inhaled tussive agents in guinea pigs. The increased cough sensitivity involves primarily an elevated sensitivity of cough sensors and also an enhanced synaptic transmission of their afferent signals at the nucleus tractus solitaries. In contrast to the observations in animal studies, both enhanced and diminished cough sensitivities to tussive agents have been reported in chronic smokers. This discrepancy is probably related to the history of chronic smoking of the individual smokers and the severity of existing airway inflammation and dysfunction. Furthermore, several other factors possibly contributing to the regulation of cough receptor sensitivity in chronic smokers should also be considered.

Cough and asthma

The relationship between cough and asthma is complex. Epidemiological studies now suggest that most children with recurrent cough who do not wheeze do not have asthma. These children are commonly described as having non-specific cough that appears to be due to increased cough receptor sensitivity during the coughing episode. Children with asthma who cough have also been shown to have increased cough receptor sensitivity during an acute exacerbation. Cough severity does not generally correlate with asthma severity. Apart from wheeze and dyspnoea, there are no clear distinguishing features to separate asthma from non-specific cough. To date, no specific treatment has clearly been shown to benefit children with non-specific cough. Although a trial of asthma treatment may be justified in these children, it is preferable to cease rather than escalate treatment if there is no response. In children with asthma who cough, cough should not be used as the predominant symptom to direct asthma therapy.

Cough Sensitivity in Pure Cough Variant Asthma Elicited Using Continuous Capsaicin Inhalation

Cough variant asthma has recently been described, mainly as airway inflammation in relation to bronchial asthma, but the relationship between the two types of asthma remains unclear. Further studies of cough receptor sensitivity are necessary to fully characterize cough variant asthma. We assessed the relevance of testing cough sensitivity using an Astograph with continuous capsaicin inhalation, and compared the results with those obtained using intermittent inhalation. We showed the clinical applicability of testing cough sensitivity (0.156-80 microM capsaicin; five or more coughs, 1 minute of continuous inhalation at each concentration) using this method. We compared cough sensitivity among patients with pure cough variant asthma who did not develop bronchial asthma after an observation period of at least 1 year, patients with bronchial asthma and healthy individuals. The continuous cough sensitivity test using the Astograph was reproducible and reliable. Cough sensitivity in patients with pure cough variant asthma was significantly higher than that in healthy individuals. The cough sensitivity of patients with cough variant asthma is not necessarily identical to that of healthy individuals.

Effect of Inspiratory Flow on Methacholine Challenge in Children

Regulation of inspiratory flow alters the outcomes of the methacholine (MHC) challenge in adults and cough receptor sensitivity in children. The effect of inspiratory flow on the reproducibility of the MHC challenge in children is unknown. The aim of this study was to evaluate the effect of inspiratory flow alteration on the repeatabilty of the MHC challenge in children with and without asthma. Twenty‐five children undertook the MHC challenge on three different days by using a dosimeter connected to a setup that allowed regulation of inspiratory flow and pattern. Children were randomized to commence the challenges at 20 or 60 L/min, and the last challenge was performed at 20 L/min. The within‐subject standard deviation, 95% range for change, and doubling dose for the differing inspiratory flow (20 vs. 60 L/min) was more than twice that of when inspiratory flow was maintained at 20 L/min for both occasions. The range of the “limits of agreement” of the Bland and Altman plot was smaller when inspiratory flow was constant. For short‐term comparative individual studies in children, inspiratory flow should be regulated. Laboratories and research measuring change in airway hyperrepsonsiveness to MHC should determine and report reproducibility indices of the challenge so airway hyperresponsiveness changes can be interpreted meaningfully.

Cough, airway inflammation, and mild asthma exacerbation

Background: Prospective data on the temporal relation between cough, asthma symptoms, and airway inflammation in childhood asthma is unavailable. Aims and methods: Using several clinical (diary, quality of life), lung...

Effects of suplatast tosilate, a new type of anti‐allergic agent, on airway cough hypersensitivity induced by airway allergy in guinea‐pigs

Cough receptor hypersensitivity is a fundamental feature of some conditions presenting with chronic non-productive cough. Suplatast tosilate, an anti-allergic agent, is a T helper (Th)2 cytokine inhibitor that inhibits the synthesis of interleukin (IL)-4, IL-5, immunoglobulin (Ig)E production, and local eosinophil accumulation. The purpose of this study was to investigate the effect of suplatast on antigen-induced airway cough hypersensitivity and eosinophil infiltration into the airway. Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10-8, 10-6 and 10-4 M) was counted 24 h after an antigen challenge in conscious guinea-pigs and then bronchoalveolar lavage was performed. We investigated the effect of single (before antigen challenge or capsaicin provocation) or repetitive treatment with intraperitoneal suplatast at a dose of 10 or 30 mg/kg on antigen-induced cough hypersensitivity. Twenty-four hours after antigen challenge, guinea-pigs developed an increase in cough receptor sensitivity to inhaled capsaicin and eosinophil infiltration in the airways. After a 2-week treatment with suplatast, but not after only a single treatment before antigen challenge or capsaicin provocation, the antigen-induced early phase bronchoconstriction, cough hypersensitivity, and airway eosinophilia were inhibited in a dose-dependent manner. These results indicate that suplatast inhibits airway cough hypersensitivity underlying allergic eosinophilic inflammation.

Comparison between tidal breathing and dosimeter methods in assessing cough receptor sensitivity to capsaicin

Comparison between tidal breathing and dosimeter methods in assessing cough receptor sensitivity to capsaicin

Comparison between tidal breathing and dosimeter methods in assessing cough receptor sensitivity to capsaicin

Dosimeter method and tidal breathing method have been used to assess cough sensitivity to inhaled capsaicin, a C-fibre ending stimulator. The aim of the present study was to evaluate the repeatability of and the agreement between the two methods. Cough threshold, the lowest concentration of capsaicin causing five or more coughs, was measured twice 1-3 weeks apart by each method in 26 normal subjects. Increasing concentrations of capsaicin were inhaled by a single breath in the dosimeter method or by 15 s tidal breathing in the tidal breathing method in 1 min intervals. Coefficients of repeatability of the cough threshold measurement were 1.89 and 2.71 doubling concentration in the tidal breathing method and the dosimeter method, respectively, suggesting good repeatability in the cough threshold measurement by both methods. The cough threshold was significantly (P < 0.0001) greater by 1.75 doubling concentration on the dosimeter method than the tidal breathing method. The coefficient of agreement between the two methods was 2.53 doubling concentration. Five subjects complained of burning sensation in the throat in the dosimeter method but no patient complained about the tidal breathing method (P < 0.05). Although the agreement between the two methods was considered to be good, higher concentrations of capsaicin solution were required to determine the cough threshold in the dosimeter method, resulting in an unpleasant sensation in the throat.

Cough, cough receptors, and asthma in children.

This review discusses current general concepts on cough and the relationship between cough, cough receptor sensitivity, and asthma in children. It presents models of the relationship between cough and bronchoconstriction, and proposes a new model outlining the relationship between cough receptor sensitivity, airway hyperresponsiveness, and the clinical issues of cough, wheeze, and dyspnea in children with and without asthma. Cough is very common in children, with a prevalence of 15-20%. Those with non-specific cough (dry cough in the absence of identifiable respiratory illness) are often treated with a variety of drugs, in particular, medications for asthma and gastroesophageal reflux. However, there is little evidence to use these medications for the sole symptom of cough in children. Clinical studies on cough need to be interpreted in light of inherent methodological problems in studying cough. These methodological problems include the nonrepeatable nature of questions on cough, the unreliability of subjective measurements of cough, the lack of objective measurements to quantify cough severity, and the period effect (spontaneous resolution of cough). Although cough can be troublesome, cough serves as an important function for maintaining normal health of the respiratory system. The importance of cough in maintaining respiratory health is reflected in the development of lung atelactasis/collapse from retained secretions and recurrent pneumonia in clinical situations where the cough reflex is ineffective. The cough reflex is complex and still poorly understood. In this article the simplified cough pathway is presented and involves cough receptors, mediators of sensory nerves and the afferent pathway, the vagus nerve, the cough centre, efferent pathway, and cough effectors.

Cough frequency and cough receptor sensitivity to citric acid challenge during a simulated ascent to extreme altitude

The aim of this study was to determine the frequency of cough and the citric acid cough threshold during hypobaric hypoxia under controlled environmental conditions. Subjects were studied during Operation Everest 3. Eight subjects ascended to a simulated altitude of 8,848 m over 31 days in a hypobaric chamber. Frequency of nocturnal cough was measured using voice-activated tape recorders, and cough threshold by inhalation of increasing concentrations of citric acid aerosol. Spirometry was performed before and after each test. Subjects recorded symptoms of acute mountain sickness and arterial oxygen saturation daily. Air temperature and humidity were controlled during the operation. Cough frequency increased with increasing altitude, from a median of 0 coughs (range 0-4) at sea level to 15 coughs (range 3-32) at a simulated altitude of 8,000 m. Cough threshold was unchanged on arrival at 5,000 m compared to sea level (geometric mean difference (GMD) 1.0, 95% confidence intervals (CI) 0.5-2.1, p=0.5), but fell on arrival at 8,000 m compared to sea level (GMD 3.3, 95% CI 1.1-10.3, p=0.043). There was no relationship between cough threshold and symptoms of acute mountain sickness, oxygen saturation or forced expiratory volume in one second. Temperature and humidity in the chamber were controlled between 18-24 degrees C and 30-60%, respectively. These results confirm an increase in cough frequency and cough receptor sensitivity associated with hypobaric hypoxia, and refute the hypothesis that high altitude cough is due to the inhalation of cold, dry air. The small sample size makes further conclusions difficult, and the cause of altitude-related cough remains unclear.

Cough receptor sensitivity to capsaicin and tartaric acid in patients with Mycoplasma pneumonia.

There has been no detailed study of cough sensitivity during acute lower respiratory infection. The aim of this study was to clarify cough sensitivity in Mycoplasma pneumonia, which is a well known acute lower respiratory infection with persistent nonproductive cough. We examined cough sensitivity to inhaled capsaicin and tartaric acid in both the acute and the convalescent phases of Mycoplasma pneumonia, cell differentials in bronchoalveolar lavage fluid, and pathologic findings of transbronchoscopic bronchial biopsy specimens. Although dry cough was observed in all patients during Mycoplasma pneumonia, cough sensitivity in the acute phase [capsaicin: 19.8 (GSEM, 0.214) microM, tartaric acid: 0.26 (GSEM, 0.356) M] were not enhanced compared with those in both control subjects [capsaicin: 27.9 (GSEM, 1.24) microM, tartaric acid: 0.316 (GSEM, 0.079) M] and patients in the convalescent phase [capsaicin: 15.7 (GSEM, 0.219) microM, tartaric acid: 0.50 (GSEM, 0.326) M] when all symptoms including cough had disappeared. The percentage of lymphocytes and neutrophils in bronchoalveolar lavage fluid BALF was significantly greater than in the control subjects, and lymphocyte-dominant bronchitis was observed in biopsied specimens. We conclude that cough threshold to inhaled capsaicin or tartaric acid was not enhanced during acute Mycoplasma pneumonia with lymphocyte-predominant bronchitis. This is the first report examining cough sensitivity in patients with acute lower respiratory infection with pneumonia.

Cough receptor sensitivity in children with acute and non-acute asthma.

BACKGROUND: Cough is a major symptom in some children with asthma. The relationship between cough and the severity of asthma is ill defined. A study was undertaken to test the...

Cough frequency and cough-receptor sensitivity are increased in man at altitude.

1. Travellers to high altitude often complain of paroxysmal cough, which has not been previously investigated. We recorded overnight cough frequency and cough-receptor sensitivity to inhaled citric acid in a group of climbers travelling to 5300 m or higher. 2. Cough frequency, monitored in ten subjects, increased from a median of 0 coughs at sea level (range 0-1) to 5 coughs at 5000 m (range 0-13) and to over 60 coughs in subjects ascending to 7000 m. Citric acid cough threshold, measured in 42 subjects, was unchanged on arrival at 5300 m compared with sea level (geometric mean difference 1.26, 95% confidence intervals 0.84-1.89, P = 0.25), but was significantly reduced after 6 days, or more, at altitude compared with sea level (geometric mean difference 2.2, 95% confidence intervals 1.54-3.15, P = 0.0002). Cough threshold was not related to symptoms of acute mountain sickness, oxygen saturation, carbon dioxide tension or lung function. 3. These results indicate an increase in cough and cough-receptor sensitivity after some days at altitude. This may be due to respiratory tract damage from breathing cold dry air at increased ventilatory rates. Other explanations, such as sub-clinical pulmonary oedema or an effect on the cough centre of acclimatization to altitude, cannot be excluded.

Airway hyperresponsiveness and cough-receptor sensitivity in children with recurrent cough.

In children, recurrent cough is a common presenting symptom that may represent asthma. We tested the hypotheses that children with recurrent cough have increased cough-receptor sensitivity (CRS) or airway hyperresponsiveness (AHR). Skin prick testing, the capsaicin CRS test, and hypertonic saline (HS) challenge were performed in 44 children (median age: 8.9 yr) with recurrent dry cough (> or = 2 episodes of cough, each lasting > or = 2 wk, within a period of 12 mo) and 44 controls. Measures of CRS were the concentration of capsaicin required to stimulate > or = 2 coughs (Cth) and > or = 5 coughs (C5). During the coughing period, Cth (mean log: 0.62 [95% CI: 0.43 to 0.81]) and C5 (mean log: 1.15 [95% CI: 0.86 to 1.44]) of the subjects without AHR were significantly lower (p = 0.0026, 0.027, respectively) than Cth (mean log: 1.27 [95% CI: 0.88 to 1.66]) and C5 (mean log: 1.79 [95% CI: 1.21 to 2.37]) of the subjects with AHR and those of the controls (p = 0.0002 and 0.0001). During the cough-free period, there was no difference in CRS among the groups. In subjects who demonstrated AHR, the provocation dose causing a > or = 15% fall in FEV1 (PD15) during the cough period was significantly lower (p = 0.005) than that during the cough-free period. We conclude that AHR or increased CRS is present during the coughing phase in children with recurrent cough.

Capsaicin cough receptor sensitivity test in children.

Capsaicin has been used as a tussive agent in studies in adults to determine cough receptor sensitivity. The aim of this study was to determine the tolerance, repeatability and influence of inspiratory flow on the capsaicin cough receptor sensitivity test in children. Thirty children (mean age 11 yrs; range 6-16 yrs) were tested on two different days, to determine the lowest concentration of capsaicin required to stimulate two or more coughs (cough threshold (Cth)), 2-4 coughs (C2), and five or more coughs (C5). Capsaicin was nebulized through a dosimeter, with an arrangement that allowed the subjects to visualize and regulate their inspiratory flow. Using a constant inspiratory flow of 20 L x min(-1), tests were reproducible for C2, C5 and Cth (doubling dose changes of 1.13, 1.03 and 1.08, respectively). An increase in the inspiratory flow from 20 to 60 L x min(-1) significantly increased C2 (19.5 to 46.8 microM; p=0.016) and C5 (46.8 to 128.8 microM; p=0.008). We conclude that in children, the capsaicin cough challenge test: 1) is well-tolerated; 2) is highly repeatable; and that 3) the inspiratory flow significantly influences cough receptor sensitivity and repeatability of the test and should, thus, be regulated.